Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19
Authors: Daniele Focosi, Emanuele Nicastri
Journal: Annals of Internal Medicine (2023)

LettersOctober 2023Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19FREEDaniele Focosi, MD, and Emanuele Nicastri, MDDaniele Focosi, MDNorth-Western Tuscany Blood Banks, Pisa University Hospital, Pisa, ItalySearch for more papers by this author, and Emanuele Nicastri, MD“Lazzaro Spallanzani” National Institute for Infectious Disease IRCCS, Rome, ItalySearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L23-0264 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: We read with interest Wan and colleagues' (1) emulation randomized controlled trial (RCT) performed during the Omicron COVID-19 waves (1). The authors reported that oral antivirals were effective at reducing 28-day all-cause mortality but not progression to ventilatory support or intensive care unit admission in patients with COVID-19 who received therapy within 5 days of hospitalization, regardless of vaccination status. These positive findings conflict with the negative results of formal RCTs. The MOVe-IN trial evaluated 304 unvaccinated hospitalized patients during the Alpha wave and reported no reduction in 29-day all-cause mortality or SARS-CoV-2 viral load and no effect on sustained recovery. Furthermore, the trial was stopped by the ethics committee after slightly higher death rates were reported in the molnupiravir group (2).Nirmatrelvir–ritonavir similarly showed no significant reduction over standard of care in the risk for all-cause mortality on day 28 or the duration of SARS-CoV-2 RNA clearance in 264 hospitalized adult patients with COVID-19 who had severe comorbid conditions in Shanghai (3). The Pfizer-sponsored EPIC-HOS (A Study to Learn About the Medicine Called Nirmatrelvir Used in Combination With Ritonavir in People With Weakened Immune Systems or at Increased Risk for Poor Outcomes Who Are Hospitalized Due to Severe COVID-19; ClinicalTrials.gov: NCT05545319), a placebo-controlled RCT of nirmatrelvir–ritonavir in hospitalized immunocompromised patients, unfortunately was discontinued on 1 March 2023 because of “operational feasibility” (4). Although a large-scale formal RCT to evaluate the efficacy of nirmatrelvir–ritonavir in inpatients has not yet been conducted, novel antivirals are under clinical assessment and considered the ideal comparator in noninferiority studies (5). Of note, antibody-based antivirals—which have been effective when administered to outpatients with COVID-19—have been proved ineffective in immunocompetent inpatients, probably marking the threshold between a pathology driven by a virus versus one driven by inflammation.Several biases not limited to residual immortal time bias could explain the mortality hazard ratio observed by Wan and colleagues. The 11.5% prevalence rate of patients with at least 3 vaccine doses (the only status that protects against mortality from the Omicron variant) was generally low in the molnupiravir group (n = 1448 [8.8%]) and particularly low in the nirmatrelvir–ritonavir group (n = 1277 [17.9%]). In addition, no information apart from cumulative data in Supplement Table 2 of Wan and colleagues' article is provided on the use of remdesivir (the internationally approved intravenous antiviral for inpatients affected by COVID-19) or the need for oxygen support in patients who have and have not received oral antivirals. If the prevalence rate of oxygen support was low, Wan and colleagues' study could be considered an emulation trial of a real-world experience in an outpatient-like setting, suggesting that oral antivirals are effective only in early stages of disease.References1. Wan EYF, Yan VKC, Mok AHY, et al. Effectiveness of molnupiravir and nirmatrelvir–ritonavir in hospitalized patients with COVID-19. A target trial emulation study. Ann Intern Med. 2023;176:505-514. [PMID: 36913693] doi:10.7326/M22-3057 LinkGoogle Scholar2. Arribas JR, Bhagani S, Lobo SM, et al; for the MOVe-IN Study Group. Randomized trial of molnupiravir or placebo in patients hospitalized with Covid-19. NEJM Evid. 2022;1. doi:10.1056/EVIDoa2100044 CrossrefGoogle Scholar3. Liu J, Pan X, Zhang S, et al. Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study. Lancet Reg Health West Pac. 2023;33. doi:10.1016/j.lanwpc.2023.100694 CrossrefGoogle Scholar4. A Study to Learn About the Medicine Called Nirmatrelvir Used in Combination With Ritonavir in People With Weakened Immune Systems or at Increased Risk for Poor Outcomes Who Are Hospitalized Due to Severe COVID-19 (EPIC-HOS). ClinicalTrials.gov: NCT05545319. Accessed at www.clinicaltrials.gov/ct2/show/NCT05545319 on 14 March 2023. Google Scholar5. Cao Z, Gao W, Bao H, et al. VV116 versus nirmatrelvir-ritonavir for oral treatment of COVID-19. N Engl J Med. 2023;388:406-417. [PMID: 36577095] doi:10.1056/NEJMoa2208822 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Daniele Focosi, MD; Emanuele Nicastri, MDAffiliations: North-Western Tuscany Blood Banks, Pisa University Hospital, Pisa, Italy“Lazzaro Spallanzani” National Institute for Infectious Disease IRCCS, Rome, ItalyDisclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L23-0264. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEffectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19 Eric Yuk Fai Wan , Vincent Ka Chun Yan , Anna Hoi Ying Mok , Boyuan Wang , Wanchun Xu , Franco Wing Tak Cheng , Francisco Tsz Tsun Lai , Celine Sze Ling Chui , Xue Li , Carlos King Ho Wong , Philip Hei Li , Benjamin John Cowling , Ivan Fan Ngai Hung , Chak Sing Lau , Ian Chi Kei Wong , and Esther Wai Yin Chan Effectiveness of Molnupiravir and Nirmatrelvir–Ritonavir in Hospitalized Patients With COVID-19 Eric Yuk Fai Wan , Vincent Ka Chun Yan , Anna Hoi Ying Mok , Ian Chi Kei Wong , Esther Wai Yin Chan Metrics October 2023Volume 176, Issue 10 Keywords Antivirals Clinical trials COVID-19 Hospitalizations Intensive care units Mortality Vaccines Ventilatory support ePublished: 17 October 2023 Issue Published: October 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. 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